Sepsis-associated encephalopathy (SAE) represents a severe neurological complication in sepsis, characterized by high mortality and cognitive impairment. Although clinical significance, SAE lacks effective diagnostic and prognostic tools. This study evaluates the predictive value of neuron-specific enolase (NSE) and regional cerebral oxygen saturation variability (rSO(2)%) as indicators for diagnosing and prognosing SAE. A prospective observational study enrolled 70 sepsis patients, classified into SAE and non-SAE groups. Serum NSE levels and rSO(2)% were measured alongside clinical data and 28-day mortality outcomes. NSE and rSO(2)% were identified as independent indicators of SAE (P < 0.05). Combined analysis achieved a higher diagnostic accuracy, with an area under the ROC curve of 0.749, compared to single indicators. Kaplan-Meier survival analysis reveals that elevated NSE levels and increased rSO(2)% are associated with significantly reduced 28-day survival (P < 0.001). These findings suggest that NSE and rSO(2)%are valuable indicators for the diagnosis and prognosticating SAE. Their combined application significantly improves diagnostic efficacy, providing a basis for personalized early intervention strategies.